Leishmanicidal effect of LLD-3 (1), a nor-triterpene isolated from Lophanthera lactescens

Danelli, M.G.M.; Soares, Deivid Costa; Abreu, H.S.; Pecanha, L. M. T.; Saraiva, Elvira M.

doi:10.1016/j.phytochem.2009.03.009

Cited by 21 publications

(8 citation statements)

References 28 publications

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“…The supernatants were collected, the parasites were removed by 5000 g centrifugation, and the cytokine concentration was determined by ELISA (BD Biosciences). Nitrite was measured with 50 μl of culture supernatants by the Griess method ( 15 ).…”

Section: Methodsmentioning

confidence: 99%

Role of protein kinase R in the killing of Leishmania major by macrophages in response to neutrophil elastase and TLR4 via TNFα and IFNβ

et al. 2014

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In cutaneous leishmaniasis, Leishmania amazonensis activates macrophage double-stranded, RNA-activated protein kinase R (PKR) to promote parasite growth. In our study, Leishmania major grew normally in RAW cells, RAW-expressing dominant-negative PKR (PKR-DN) cells, and macrophages of PKR-knockout mice, revealing that PKR is dispensable for L. major growth in macrophages. PKR activation in infected macrophages with poly I:C resulted in parasite death. Fifty percent of L. major-knockout lines for the ecotin-like serine peptidase inhibitor (ISP2; Δisp2/isp3), an inhibitor of neutrophil elastase (NE), died in RAW cells or macrophages from 129Sv mice, as a result of PKR activation. Inhibition of PKR or NE or neutralization of Toll-like receptor 4 or 2(TLR4 or TLR2) prevented the death of Δisp2/isp3. Δisp2/isp3 grew normally in RAW-PKR-DN cells or macrophages from 129Sv pkr−/−, tlr2−/−, trif−/−, and myd88−/− mice, associating NE activity, PKR, and TLR responses with parasite death. Δisp2/isp3 increased the expression of mRNA for TNF-α by 2-fold and of interferon β (IFNβ) in a PKR-dependent manner. Antibodies to TNF-α reversed the 95% killing by Δisp2/isp3, whereas they grew normally in macrophages from IFN receptor–knockout mice. We propose that ISP2 prevents the activation of PKR via an NE-TLR4-TLR2 axis to control innate responses that contribute to the killing of L. major.—Faria, M. S., Calegari-Silva, T. C., de Carvalho Vivarini, A., Mottram, J. C., Lopes, U. G., Lima, A. P. C. A. Role of protein kinase R in the killing of Leishmania major by macrophages in response to neutrophil elastase and TLR4 via TNFα and IFNβ.

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Section: Methodsmentioning

confidence: 99%

Role of protein kinase R in the killing of Leishmania major by macrophages in response to neutrophil elastase and TLR4 via TNFα and IFNβ

et al. 2014

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“…The nor-triterpene 6 α ,7 α ,15 β ,16 β ,24-pentacetoxy-22 α -carbometoxy-21 β ,22 β -epoxy-18 β -hydroxy-27,30-bisnor-3,4-secofriedela-1,20(29)-dien-3,4 R-olide (LLD-3), extracted from Lophanthera lactescens Ducke, showed a remarkable antileishmanial activity against intracellular amastigotes (IC 50 = 0.41 μ g/mL) but no cytotoxicity to mouse peritoneal macrophages or B cells, which makes it a promising drug candidate for leishmaniasis treatment [ 54 ]. In addition, piperine ( Figure 1 ), the main alkaloid of Piper nigrum , and its analogue phenylamide are active against L. amazonensis promastigotes and amastigotes.…”

Section: Natural Products Effects On Host Immunological Responsementioning

confidence: 99%

Natural Products: Insights into Leishmaniasis Inflammatory Response

Rodrigues

Mazotto

Cardoso

et al. 2015

Mediators of Inflammation

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Leishmaniasis is a vector-borne disease that affects several populations worldwide, against which there are no vaccines available and the chemotherapy is highly toxic. Depending on the species causing the infection, the disease is characterized by commitment of tissues, including the skin, mucous membranes, and internal organs. Despite the relevance of host inflammatory mediators on parasite burden control, Leishmania and host immune cells interaction may generate an exacerbated proinflammatory response that plays an important role in the development of leishmaniasis clinical manifestations. Plant-derived natural products have been recognized as bioactive agents with several properties, including anti-protozoal and anti-inflammatory activities. The present review focuses on the antileishmanial activity of plant-derived natural products that are able to modulate the inflammatory response in vitro and in vivo. The capability of crude extracts and some isolated substances in promoting an anti-inflammatory response during Leishmania infection may be used as part of an effective strategy to fight the disease.

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“…Nitrite, the end product of NO metabolism, was measured from 50 l of cell culture supernatants by using Griess reagent, as described elsewhere (32).…”

Section: Determination Of Nitrite Concentrationmentioning

confidence: 99%

Novel role for the double‐stranded RNA‐activated protein kinase PKR: modulation of macrophage infection by the protozoan parasiteLeishmania

et al. 2009

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The evolution of Leishmania infection depends on the balance between microbicidal and suppressor macrophage functions. Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a classic antiviral protein, is able to regulate a number of signaling pathways and macrophage functions. We investigated the possible role of PKR in the modulation of Leishmania infection. Our data demonstrated that Leishmania amazonensis infection led to PKR activation and increased PKR levels. Consistently, in macrophages from PKR knockout 129Sv/Ev mice and RAW-264.7 cells stably expressing a dominant-negative (DN) construct of PKR (DN-PKR), L. amazonensis infection was strongly reduced. The treatment of infected macrophages with the synthetic double-stranded RNA poly(I:C), a potent PKR inductor, increased L. amazonensis intracellular proliferation. This effect was reversed by 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, as well as by the expression of DN-PKR. NO release induced by dsRNA treatment was inhibited by L. amazonensis through NF-kappaB modulation. PKR activation induced by dsRNA also resulted in IL-10 production, whose neutralization with specific antibody completely abrogated L. amazonensis proliferation. Our data demonstrated a new role of PKR in protozoan parasitic infection through IL-10 modulation.

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Leishmanicidal effect of LLD-3 (1), a nor-triterpene isolated from Lophanthera lactescens

Cited by 21 publications

References 28 publications

Role of protein kinase R in the killing of Leishmania major by macrophages in response to neutrophil elastase and TLR4 via TNFα and IFNβ

Role of protein kinase R in the killing of Leishmania major by macrophages in response to neutrophil elastase and TLR4 via TNFα and IFNβ

Natural Products: Insights into Leishmaniasis Inflammatory Response

Novel role for the double‐stranded RNA‐activated protein kinase PKR: modulation of macrophage infection by the protozoan parasiteLeishmania

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